CRF is a 41-amino acid linear peptide isolated from ovine hypothalmia. CRF plays a crucial role in integrating the body's overall response to stress. Although the existence of CRF was postulated more than thirty years ago (G. W. Harris, Physiol. Rev. 28:139), its purification and sequencing was reported in 1981 (W. Vale et al., Science, 213, 1394 (1981); J. Spiess et al. Proc. Natl. Acad. Sci., U.S.A., 78, 6517 (1981)). Shortly thereafter the sequences of human and rat CRF were determined and these were found to be the same, but differed from ovine CRF (oCRF) in 7 of the 41 amino acid residues (J. Rivier et al. Proc. Natl. Acad. Sci., U.S.A., 80, 4851 (1983)); Furutani et al. Nature, 301, 537 (1983). CRF produces profound alterations in behavioral and autonomic nervous system functions (M. R. Brown and L. A. Fisher, Fed. Proc., 44, 243 (1985); G. F. Koob, F. E. Bloom, Fed. Proc., 44, 259 (1985)). Upon direct administration into the brain, CRF initiates behavioral, physiological and endocrine responses that are essentially identical to those observed when animals are exposed to stressful environment. When given, for example, by intracerebroventricular (icv) injection, CRF induces behavioral activation (R. E. Sutton et al. Nature 297, 331 (1982)), it produces a long-lasting activation of the electroencephalogram (C. L. Ehlers, et al. Brain Res. 278, 332 (1983)), stimulates the sympathoadrenomodullary pathway (M. R. Brown et al. Endocrinology 110, 928 (1982)), increases heart rate, raises blood pressure and increases oxygen consumption (L. A. Fisher et al. Endocrinology 1 10, 2222 (1982)), alters gastrointestinal activity (M. R. Brown et al. Life Sciences 30, 207 (1982), suppresses food intake (C. L. Williams et al. Am. J Physiol, 253, G582 (1987) and sexual behavior (A. S. Levine et al. Neuropharmacology, 22, 337 (1983)), and affects immune function (D. J. S. Sirinathsinghji et al. Nature, 305, 232 (1983); M. Irwin et al. Am. J. Physiol. 225, R744 (1988).
The actions of CRF in the peripheral and central nervous system are media ted through multiple binding sites. These CRF binding sites are heterogeneous with respect to sequence, pharmacology, and tissue distribution. Three CRF receptors, CRF.sub.1, CRF.sub.2.alpha. and CRF.sub.2.beta., which encode 411-, 415-, and 431-amino acid proteins respectively, have been reported to date. The reported CRF receptors comprise seven putative membrane-spanning domains characteristic of G.sub.s -coupled receptors. All three CRF receptors transduce a signal which involves stimulation of cAMP production.
A few classes of non-peptide CRF receptor antagonists have been reported in the past few years. Derivatives of 4-substituted thio-5-oxo-3-pyrazolines have been disclosed as CRF antagonists in U.S. Pat. No. 5,420,133. A weakly potent class of CRF antagonists has been reported in European patent application EP 0576350A1 (1993). Series of patent applications (WO 94/13643, WO 94/136344, WO 94/13661 and WO 94/13677) claiming non-peptide compounds as CRF antagonists have been reported by Pfizer and Co., Inc. The duPont Merck pharmaceutical company has recently disclosed a class of CRF antagonists, 1N-alkyl-N-arylpyrimidines and their derivatives in international patent application WO 95/10506.